Skip to main content
PMC home page
BMC Cancer logoLink to BMC Cancer
. 2020 Jul 24;20:689. doi: 10.1186/s12885-020-07139-y

Effect of diabetes mellitus on survival in patients with gallbladder Cancer: a systematic review and meta-analysis

Chen Jing 1, Zhengyi Wang 1, Xue Fu 1,✉
PMCID: PMC7379826  PMID: 32709224

Abstract

Background

Increasing evidences indicated that diabetes might increase the incidence of gallbladder cancer. However, no sufficient data has ever clarified the impact of diabetes on the survival of patients with gallbladder cancer.

Methods

We comprehensively searched PubMed, Embase, and the Cochrane Library databases through July 2019 in order to find sufficient eligible researches. The pooled hazard risks (HRs) and relative risks (RRs) with 95% confidence intervals (CIs) were calculated with either fix-effects or random-effects model. Due to the low gallbladder cancer mortality in general population, the RRs and standard mortality ratios (SMRs) were considered the similar estimates of the HRs.

Results

Ten eligible studies were included in this meta-analysis. Analysis of eight cohorts found that diabetes was closely associated with the mortality of gallbladder cancer (HR = 1.10; 95% CI: 1.06–1.14; P < 0.00001). However, the mortality in male diabetes patients was not higher than female patients (RR = 1.08, 95%CI = 0.57–2.04, P = 0.80).

Conclusions

These findings indicated that diabetes patients had a higher mortality of gallbladder cancer compared with non-diabetes.

Keywords: Gallbladder cancer, Diabetes mellitus, Mortality, Meta-analysis

Background

Gallbladder cancer (GBC) is one of the most common biliary tract malignancies worldwide [1]. By and large, poor prognosis seriously affects the mortality of patients with gallbladder cancer [2]. Gallbladder cancer patients survive the mean survival rate of 6 months and a 5-year survival rate of 5% [3]. Generally, women are two to six times more likely to be attacked by gallbladder cancer [4]. The prognosis of patients with GBC is affected by a growing number of factors, including age, gender, smoking, ethnic, and menopause [5–9]. Advancing age partly demonstrates the prevalence of gallbladder cancer [10]. Finding an optimal prognostic indicator would be helpful to improve the survival rate of GBC.

Diabetes mellitus (DM) is a costly chronic disease worldwide. The incremental increase in costs of this disease have laid economic burdens on both financial expenditure in most countries and patients themselves. In the United State, the newly diagnosed patients spent approximately $8941 more than subjects who were not diagnosed with DM over a period of 5 years [11]. Approximately 415 million people suffered from diabetes in 2015 while 5 million patients died from diabetes [12]. By 2040, the number of diabetes patients are predicted to ascend to 642 million. DM is always regarded as a pivotal risk factor linked to cancer at different sites, including lung [13], liver [14], esophagus [15], stomach [16], colorectum [17], kidney [18], breast [19], leukemia, non-Hodgkin lymphoma, myeloma [20], ovary [21], and prostate [22]. As several studies and meta-analyses have pointed out, DM was closely associated with the onset risk of gallbladder cancer [23, 24]. However, rare study has focused on the relationship between DM and the mortality of gallbladder cancer. This meta-analysis aimed to figure out if DM patients had a higher risk of dying from GBC and if male and female patients had a different risk of die from GBC.

Methods

Search strategy

A comprehensive search has been made on the PubMed, Embase, web of science, and the Cochrane Library databases to find all the eligible studies up to July 13th 2019. The following text words were used in the PubMed: (“diabetes” OR “glucose intolerance” OR “insulin resistance” OR “hyperglycemia” OR “hyperinsulinemia” OR “metabolic syndrome”) AND (“gallbladder cancer” OR “gallbladder carcinoma” OR “gall bladder cancer” OR “gall bladder carcinoma”). Correlative key words were used in the Embase, web of secience, and the Cochrane Library. To comprehensively search eligible studies, we simultaneously searched the reference lists of relevant reviews or included publications for further studies.

Inclusion and exclusion criteria

The included literatures met the following criteria: (1) cohort design; (2) investigated gallbladder cancer outcomes; (3) assessed the gallbladder cancer mortality with or without DM; (4) reported the information of hazard ratios (HRs), relative risks (RRs), or standard mortality ratios (SMRs). The exclusion criteria were as follows: (1) case-control or cross-sectional design; (2) unavailable data.

Data extraction

Two authors independently extracted all data from publications using the same criteria. The following data were included: the first author’s name, publication year, country, sample size, the number of male or female participants, mean age at baseline, average follow-up duration, diabetes assessment, and adjusted factors.

Statistical analysis

We used Reviewer Manager 5.3 in this meta-analysis to analyze the data. The pooled HRs with 95% CIs were calculated as the effect estimates for the relationship between DM and gallbladder cancer mortality. The fixed-model was used when the heterogeneity was low, while the random-model was used when the heterogeneity was high. Owing to the low gallbladder cancer mortality in general population, the RRs, SMR were considered the similar estimates of the HRs [25]. Statistical heterogeneity among studies was assessed by the I2 and Q statistics. Both I2 > 50% and P value< 0.1 were regarded as high heterogeneity. We conducted subgroup analysis to evaluate the potential sources of heterogeneity from country, follow-up duration, diabetes assessment, and adjusted factors (including BMI, smoking, and education). A sensitivity analysis was performed by removing each study from the overall analysis to investigate the influence of a single study. We used funnel plots, Begg and Egger tests to assess publication bias. P value< 0.05 was viewed as a significant level. The statistical analyses were performed with Stata software (version 12.0).

Results

Study selection

Detailed study selection process was described in Fig. 1. From the initial search, we searched and identified 561 records. Two authors independently assessed the search outputs based on the primary research title or abstract. Three hundred forty-seven articles were discarded for the sake of duplication. One hundred seventy-five articles were excluded based on title or abstract. Then we read the full-text of the remaining paper. We further removed 14 studies that enrolled single-arm DM patients. Fifteen of the 25 remaining studies were subsequently removed due to lack of eligible data. Finally, a total of 10 studies were included in the meta-analysis [26–35].

Fig. 1.

Fig. 1

Open in a new tab

Flow-chart of study selection for the meta-analysis

Study characteristics

The baseline characteristics of the included studies were listed in Table 1. A total of 5,522,636 participants were included in all 10 studies. Two studies were conducted in the USA, two in the UK, three in the Asia, one in Australia, and two were international conducted studies. The average follow-up duration ranged from 2 to 18 years. Diabetes assessment methods included self-report, medical record, WHO diagnostic criteria, and read code classification. Eight studies reported the relationship between DM and gallbladder cancer mortality, while four studies assessed the different gallbladder cancer mortality in male and female DM patients.

Table 1.

Characteristic of studies included in the meta-analysis

First author, publication year Country Sample size Male/female Mean age (year) Average follow-up duration (year) Effect measure Diabetes assessment Adjusted factors
Coughlin, 2004 [26] USA 1,056,243 467,922/588321 56.7 12.5 RR Self-report Age, smoking, race, BMI, exercise, education
Yagyu, 2004 [27] Japan 113,394 47,673/65721 40–89 9.7 HR Self-report Age, gender, history of hepatic disease
Swerdlow, 2005 [28] UK 28,900 15,688/13212 NA 18.0 SMR Medical record Age, region, duration
Tseng, 2009 [34] Taiwan 244,920 113,347/131573 NA 12 SMR Medical record Age, gender
Lam, 2011 [29] Asia, Australia 367,361 216,743/150618 48 4 HR Self-report or WHO diagnostic criteria Age
Seshasai, 2011 [30] Members of ERFC 820,900 426,868/394032 55 NA HR Medical record Age, gender, smoking, BMI
Campbell, 2012 [35] USA 1,053,831 467,143/586688 63.1 12.1 RR Self-report Age, BMI, education, exercise, NSAIDs, alchhol
Currie, 2012 [31] UK 112,408 54,086/58322 67.8 2 HR Read code classification Age, gender, smoking, Charlson comorbidity index, year of diagnosis
Harding, 2015 [32] Australia 953,382 506,312/447070

T1DM: 27.4

T2DM: 60.4

 10 SMR Medical record Age
Chen, 2017 [33] Asia 771,297 391,619/379678 53.9 12.7 HR Self-report Age, gender, BMI, smoking, alcohol, education, region
Open in a new tab

ERFC Emerging Risk Factors Collaboration, T1DM Type 1 Diabetes Mellitus, T2DM Type 2 Diabetes Mellitus, RR Relative Risk, HR Hazard Ratio, SMR Standard Mortality Ratio, WHO World Health Organization, BMI Body Mass Index, NSAIDs Nonsteroidal Anti-inflammatory Drugs

The quality assessment results were shown in Figs. 2 and 3. All of the studies applied random sequence generation and allocation concealment. No attrition bias and reporting bias were reported. Two of all studies completed blinding of outcome assessment. Only one study reported performance bias.

Fig. 2.

Fig. 2

Open in a new tab

Overall risk of bias of the 10 included studies

Fig. 3.

Fig. 3

Open in a new tab

Risk of bias graph of the 10 included studies

DM and gallbladder cancer mortality

Eight studies focused on the relationship between diabetes mellitus and gallbladder cancer mortality. We merged the data of these studies and found that pre-existing diabetes had a high correlation with the mortality of gallbladder cancer compared with non-DM participants (HR = 1.10; 95% CI: 1.06–1.14; P < 0.00001; Fig. 4). A fix-effects model was applied owing to low heterogeneity (I2 = 0%; P = 0.95). The sensitivity analysis results indicated that the summary HR ranged from 1.09 (95%CI: 1.06–1.13) when excluding study from Chen 2017 to 1.12 (95%CI: 1.07–1.17) when excluding study from Currie 2012 [31, 33].

Fig. 4.

Fig. 4

Open in a new tab

Association between diabetes mellitus and the mortality of gallbladder cancer

Subgroup analysis were conducted according to country, follow-up duration, diabetes assessment, and adjustment for confounding factors, including BMI, smoking, and education. All of the results were demonstrated in Table 2. However, no evidence indicated that there were significant differences between subgroups based on factors above.

Table 2.

Subgroup analysis of relative risk for gallbladder cancer mortality in DM patients

Subgroup No. of references HR and 95% CI Pa I2% Pb
Country
 Western countries 4 1.09 (1.05–1.13) < 0.0001 0% 0.29
 Eastern countries 2 1.10 (1.06–1.13) 0.001 0%
Follow-up duration
 ≦10 4 1.03 (0.89–1.20) 0.70 84% 0.27
 > 10 3 1.13 (1.06–1.21) 0.0005 0%
Diabetes assessment
 Self-report 3 1.14 (1.06–1.22) 0.0003 0% 0.34
 Medical record 3 1.01 (0.81–1.27) 0.92 73%
Adjusted BMI
 Yes 3 1.14 (1.07–1.21) < 0.0001 0% 0.30
 No 5 1.04 (0.90–1.21) 0.57 78%
Adjusted smoking
 Yes 4 1.10 (1.05–1.14) < 0.0001 0% 0.63
 No 4 1.05 (0.87–1.26) 0.64 44%
Adjusted education
 Yes 2 1.13 (1.05–1.21) 0.0007 0% 0.43
 No 6 1.06 (0.93–1.21) 0.35 78%
Open in a new tab

Pa P value for heterogeneity within subgroup, Pb P value for subgroup differences

DM and gallbladder cancer mortality in men and women

A total of four studies estimated the difference of gallbladder cancer mortality between male and female DM patients. The analysis was conducted to see if female DM patients had a higher risk of gallbladder cancer mortality then male patients. The pooled analysis results demonstrated that no significant differences had existed between DM men and women (RR = 1.08, 95%CI = 0.57–2.04, P = 0.80; Fig. 5.). A random-effect model was applied due to high heterogeneity (P = 0.0007, I2 = 82%).

Fig. 5.

Fig. 5

Open in a new tab

Different mortality of gallbladder cancer between male and female diabetes patients

Publication bias

The symmetric funnel plots indicated a potential low publication bias (Fig. 6). Moreover, Egger test (P = 0.371) and Begg test (P = 0.845) showed no significant evidence of publication bias.

Fig. 6.

Fig. 6

Open in a new tab

Funnel plot analysis of all the studies about the association between diabetes and gallbladder cancer

Discussion

This meta-analysis of cohort studies provided comprehensive evidence that the diabetes mellitus had an impact on the survival of patients with gallbladder cancer. Our results suggested that diabetes patients had a higher mortality rate of gallbladder cancer compared with non-diabetes patients. And the results were independent of country, follow-up duration, diabetes assessment, BMI, smoking, or education. Though previous analysis had indicated that DM women were more likely to develop gallbladder cancer than DM men due to sex hormones [36], we found no obvious differences between male and female diabetes patients in gallbladder cancer mortality. However, the results remained to be tested due to lack of eligible data.

Several physiological mechanisms might account for the increase of gallbladder cancer mortality in DM patients. A growing number of studies have found that overweight, obesity, metabolic syndrome, and insulin resistance were closely related to the increase of gallbladder disease [37–39]. Hyperinsulinemia was also a phenomenon commonly existed in DM patients. Excess insulin directly or indirectly regulated the activity of insulin-like growth factor-1 (IGF-1), which was an important cytokine that influenced the development and progression of cancer [40]. Both in vitro and in vivo researches have proved that up-regulation of IGF-1 contributed to the proliferation of bile duct cancer cells and the inhibition of apoptosis [41, 42]. In addition, diabetes impaired the function of gallbladder emptying. The gallbladder smooth muscle cells of DM patients have reduced sensitivity to cholecystokinin. Meanwhile, the number of cholecystokinin receptors on the gallbladder wall in DM patients was also reduced [43]. These physiological mechanisms were consistent with the increased risk of biliary tract cancer [44].

To our knowledge, our meta-analysis was the first study focused on the impact of DM on the survival of patients with gallbladder cancer. Previous study has proved that diabetes might increase the risk of gallbladder diseases [45]. One meta-analysis has proved the association between DM and the increased GBC risk [24]. However, the meta-analysis included both case-control studies and cohort studies, which might somehow increase the overall heterogeneity. Furthermore, the majority of the included cohort studies focused on the gallbladder cancer incidence rather than mortality. Our analysis attempted to find an optimal prognostic indicator that would increase the GBC mortality. In addition, a subgroup analysis was conducted to see the difference of GBC mortality in male and female DM patients.

The present meta-analyses had some strengths, including prospective design of cohort studies, eligible data from large sample size, detailed subgroup analyses, and low heterogeneity. Our findings provided an important message for patients with comorbid DM and gallbladder cancer that preventing the progression of diabetes might increase the survival from gallbladder cancer.

There were several potential limitations in our study. First, residual confounding could not be ignored. Compared with non-DM participants, DM patients often had less healthy lifestyles, including higher rate of obesity, less physically activity, and more likely to smoke and drink. Though most of the included studies have adjusted these factors and our subgroup analysis showed no obvious heterogeneity between subgroups, we could not completely exclude the influence of these factors. Second, most studies did not tell the differences between type 1 and type 2 DM, though the majority of individuals were type 2 survivals. Older individuals were more likely to develop type 2 DM, while type 1 DM was a more common type in younger individuals. As a result of incomplete initial data on distinguishing this difference, some degree of inaccuracy of results was inevitable. Third, the number of eligible literatures remained low, which might have some influence on the final conclusion. The results of the difference of gallbladder cancer mortality between male and female patients remained open to question due to the lack of data and a high heterogeneity. Forth, the effect of medicine had not taken into account in the researches. Many studies have indicated that metformin, a commonly used diabetic medication, could retard the development of some cancers. None of the included researches have made adjustments for the use of diabetic medication. Last but not least, the multiplicity might exist in this analysis. The multiplicity attributed to a number of factors. On one hand, the subjects came from various backgrounds. Different rate, country, and age aggravated the multiplicity. On the other hand, the subjects from different studies might have an overlap.

Conclusion

In conclusion, this meta-analysis suggested that diabetes patients had a higher mortality of gallbladder cancer. More relevant studies were needed to certify this association and tell the difference between men and women.

Acknowledgements

Not applicable.

Declarations

There is no conflict of interests.

Abbreviations

HRs

Hazard risks

RRs

Relative risks

CIs

Confidence intervals

DM

Diabetes mellitus

ORs

Odd ratios

SMRs

Standard mortality ratios

BMI

Body mass index

IGF-1

Insulin-like growth factor-1

ERFC

Emerging Risk Factors Collaboration

T1DM

Type 1 Diabetes Mellitus

T2DM

Type 2 Diabetes Mellitus

WHO

World Health Organization

NSAIDs

Nonsteroidal Anti-inflammatory Drugs

Authors’ contributions

CJ and ZYW collected and analyzed all the included data. XF designed this study and drafted the manuscript. All of the authors approved the final manuscript.

Funding

No funding was obtained for this study.

Availability of data and materials

All data generated in this analysis are available from the corresponding author.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

References

  • 1.Wernberg JA, Lucarelli DD. Gallbladder cancer. Surg Clin North Am. 2014;94(2):343–360. doi: 10.1016/j.suc.2014.01.009. [DOI] [PubMed] [Google Scholar]
  • 2.Jarnagin WR, Fong Y, DeMatteo RP, Gonen M, Burke EC, Bodniewicz BJ, Youssef BM, Klimstra D, Blumgart LH. Staging, resectability, and outcome in 225 patients with hilar cholangiocarcinoma. Ann Surg. 2001;234(4):507–517. doi: 10.1097/00000658-200110000-00010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Levy AD, Murakata LA, Rohrmann CA., Jr Gallbladder carcinoma: radiologic-pathologic correlation. Radiographics. 2001;21(2):295–314. doi: 10.1148/radiographics.21.2.g01mr16295. [DOI] [PubMed] [Google Scholar]
  • 4.Konstantinidis IT, Deshpande V, Genevay M, Berger D, Fernandez-del Castillo C, Tanabe KK, Zheng H, Lauwers GY, Ferrone CR. Trends in presentation and survival for gallbladder cancer during a period of more than 4 decades: a single-institution experience. Arch Surg. 2009;144(5):441–447. doi: 10.1001/archsurg.2009.46. [DOI] [PubMed] [Google Scholar]
  • 5.Wiseman M. The second World Cancer Research Fund/American Institute for Cancer Research expert report. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Proc Nutr Soc. 2008;67(3):253–256. doi: 10.1017/S002966510800712X. [DOI] [PubMed] [Google Scholar]
  • 6.Freedman ND, Silverman DT, Hollenbeck AR, Schatzkin A, Abnet CC. Association between smoking and risk of bladder cancer among men and women. Jama. 2011;306(7):737–745. doi: 10.1001/jama.2011.1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Dietrich K, Demidenko E, Schned A, Zens MS, Heaney J, Karagas MR. Parity, early menopause and the incidence of bladder cancer in women: a case-control study and meta-analysis. Eur J Cancer. 2011;47(4):592–599. doi: 10.1016/j.ejca.2010.10.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Stern MC, Lin J, Figueroa JD, Kelsey KT, Kiltie AE, Yuan JM, Matullo G, Fletcher T, Benhamou S, Taylor JA, et al. Polymorphisms in DNA repair genes, smoking, and bladder cancer risk: findings from the international consortium of bladder cancer. Cancer Res. 2009;69(17):6857–6864. doi: 10.1158/0008-5472.CAN-09-1091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014;6:99–109. doi: 10.2147/CLEP.S37357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Duffy A, Capanu M, Abou-Alfa GK, Huitzil D, Jarnagin W, Fong Y, D'Angelica M, Dematteo RP, Blumgart LH, O'Reilly EM. Gallbladder cancer (GBC): 10-year experience at memorial Sloan-Kettering Cancer Centre (MSKCC) J Surg Oncol. 2008;98(7):485–489. doi: 10.1002/jso.21141. [DOI] [PubMed] [Google Scholar]
  • 11.Khan T, Yang J, Wozniak G. Trends in medical expenditures prior to diabetes diagnosis: the early Burden of diabetes. Popul Health Manag. 2020;0:1–6. [DOI] [PMC free article] [PubMed]
  • 12.Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, Cavan D, Shaw JE, Makaroff LE. IDF diabetes atlas: global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 2017;128:40–50. doi: 10.1016/j.diabres.2017.03.024. [DOI] [PubMed] [Google Scholar]
  • 13.Lee JY, Jeon I, Lee JM, Yoon JM, Park SM. Diabetes mellitus as an independent risk factor for lung cancer: a meta-analysis of observational studies. Eur J Cancer. 2013;49(10):2411–2423. doi: 10.1016/j.ejca.2013.02.025. [DOI] [PubMed] [Google Scholar]
  • 14.Wang C, Wang X, Gong G, Ben Q, Qiu W, Chen Y, Li G, Wang L. Increased risk of hepatocellular carcinoma in patients with diabetes mellitus: a systematic review and meta-analysis of cohort studies. Int J Cancer. 2012;130(7):1639–1648. doi: 10.1002/ijc.26165. [DOI] [PubMed] [Google Scholar]
  • 15.Huang W, Ren H, Ben Q, Cai Q, Zhu W, Li Z. Risk of esophageal cancer in diabetes mellitus: a meta-analysis of observational studies. Cancer Causes Control. 2012;23(2):263–272. doi: 10.1007/s10552-011-9874-9. [DOI] [PubMed] [Google Scholar]
  • 16.Ge Z, Ben Q, Qian J, Wang Y, Li Y. Diabetes mellitus and risk of gastric cancer: a systematic review and meta-analysis of observational studies. Eur J Gastroenterol Hepatol. 2011;23(12):1127–1135. doi: 10.1097/MEG.0b013e32834b8d73. [DOI] [PubMed] [Google Scholar]
  • 17.Jiang Y, Ben Q, Shen H, Lu W, Zhang Y, Zhu J. Diabetes mellitus and incidence and mortality of colorectal cancer: a systematic review and meta-analysis of cohort studies. Eur J Epidemiol. 2011;26(11):863–876. doi: 10.1007/s10654-011-9617-y. [DOI] [PubMed] [Google Scholar]
  • 18.Chen L, Li H, Gu L, Ma X, Li X, Gao Y, Zhang Y, Shen D, Fan Y, Wang B, et al. The impact of diabetes mellitus on renal cell carcinoma prognosis: a meta-analysis of cohort studies. Medicine. 2015;94(26):e1055. doi: 10.1097/MD.0000000000001055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer. 2007;121(4):856–862. doi: 10.1002/ijc.22717. [DOI] [PubMed] [Google Scholar]
  • 20.Castillo JJ, Mull N, Reagan JL, Nemr S, Mitri J. Increased incidence of non-Hodgkin lymphoma, leukemia, and myeloma in patients with diabetes mellitus type 2: a meta-analysis of observational studies. Blood. 2012;119(21):4845–4850. doi: 10.1182/blood-2011-06-362830. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Lee JY, Jeon I, Kim JW, Song YS, Yoon JM, Park SM. Diabetes mellitus and ovarian cancer risk: a systematic review and meta-analysis of observational studies. Int J Gynecol Cancer. 2013;23(3):402–412. doi: 10.1097/IGC.0b013e31828189b2. [DOI] [PubMed] [Google Scholar]
  • 22.Jian Gang P, Mo L, Lu Y, Runqi L, Xing Z. Diabetes mellitus and the risk of prostate cancer: an update and cumulative meta-analysis. Endocr Res. 2015;40(1):54–61. doi: 10.3109/07435800.2014.934961. [DOI] [PubMed] [Google Scholar]
  • 23.Zhu Z, Zhang X, Shen Z, Zhong S, Wang X, Lu Y, Xu C. Diabetes mellitus and risk of bladder cancer: a meta-analysis of cohort studies. PLoS One. 2013;8(2):e56662. doi: 10.1371/journal.pone.0056662. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Gu J, Yan S, Wang B, Shen F, Cao H, Fan J, Wang Y. Type 2 diabetes mellitus and risk of gallbladder cancer: a systematic review and meta-analysis of observational studies. Diabetes Metab Res Rev. 2016;32(1):63–72. doi: 10.1002/dmrr.2671. [DOI] [PubMed] [Google Scholar]
  • 25.Zhu Z, Wang X, Shen Z, Lu Y, Zhong S, Xu C. Risk of bladder cancer in patients with diabetes mellitus: an updated meta-analysis of 36 observational studies. BMC Cancer. 2013;13:310. doi: 10.1186/1471-2407-13-310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Coughlin SS, Calle EE, Teras LR, Petrelli J, Thun MJ. Diabetes mellitus as a predictor of cancer mortality in a large cohort of US adults. Am J Epidemiol. 2004;159(12):1160–1167. doi: 10.1093/aje/kwh161. [DOI] [PubMed] [Google Scholar]
  • 27.Yagyu K, Lin Y, Obata Y, Kikuchi S, Ishibashi T, Kurosawa M, Inaba Y, Tamakoshi A. Bowel movement frequency, medical history and the risk of gallbladder cancer death: a cohort study in Japan. Cancer Sci. 2004;95(8):674–678. doi: 10.1111/j.1349-7006.2004.tb03328.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Swerdlow AJ, Laing SP, Qiao Z, Slater SD, Burden AC, Botha JL, Waugh NR, Morris AD, Gatling W, Gale EA, et al. Cancer incidence and mortality in patients with insulin-treated diabetes: a UK cohort study. Br J Cancer. 2005;92(11):2070–2075. doi: 10.1038/sj.bjc.6602611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.Lam EK, Batty GD, Huxley RR, Martiniuk AL, Barzi F, Lam TH, Lawes CM, Giles GG, Welborn T, Ueshima H, et al. Associations of diabetes mellitus with site-specific cancer mortality in the Asia-Pacific region. Ann Oncol. 2011;22(3):730–738. doi: 10.1093/annonc/mdq405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Rao Kondapally Seshasai S, Kaptoge S, Thompson A, Di Angelantonio E, Gao P, Sarwar N, Whincup PH, Mukamal KJ, Gillum RF, Holme I, et al. Diabetes mellitus, fasting glucose, and risk of cause-specific death. N Engl J Med. 2011;364(9):829–841. doi: 10.1056/NEJMoa1008862. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31.Currie CJ, Poole CD, Jenkins-Jones S, Gale EA, Johnson JA, Morgan CL. Mortality after incident cancer in people with and without type 2 diabetes: impact of metformin on survival. Diabetes Care. 2012;35(2):299–304. doi: 10.2337/dc11-1313. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Harding JL, Shaw JE, Peeters A, Cartensen B, Magliano DJ. Cancer risk among people with type 1 and type 2 diabetes: disentangling true associations, detection bias, and reverse causation. Diabetes Care. 2015;38(2):264–270. doi: 10.2337/dc14-1996. [DOI] [PubMed] [Google Scholar]
  • 33.Chen Y, Wu F, Saito E, Lin Y, Song M, Luu HN, Gupta PC, Sawada N, Tamakoshi A, Shu X-O, et al. Association between type 2 diabetes and risk of cancer mortality: a pooled analysis of over 771,000 individuals in the Asia cohort consortium. Diabetologia. 2017;60(6):1022–1032. doi: 10.1007/s00125-017-4229-z. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Tseng CH, Chong CK, Tseng CP, Chan TT. Age-related risk of mortality from bladder cancer in diabetic patients: a 12-year follow-up of a national cohort in Taiwan. Ann Med. 2009;41(5):371–379. doi: 10.1080/07853890902729778. [DOI] [PubMed] [Google Scholar]
  • 35.Campbell PT, Newton CC, Patel AV, Jacobs EJ, Gapstur SM. Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults. Diabetes Care. 2012;35(9):1835–1844. doi: 10.2337/dc12-0002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Gabbi C, Kim HJ, Barros R, Korach-Andre M, Warner M, Gustafsson JA. Estrogen-dependent gallbladder carcinogenesis in LXRbeta−/− female mice. Proc Natl Acad Sci U S A. 2010;107(33):14763–14768. doi: 10.1073/pnas.1009483107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Abdullah A, Peeters A, de Courten M, Stoelwinder J. The magnitude of association between overweight and obesity and the risk of diabetes: a meta-analysis of prospective cohort studies. Diabetes Res Clin Pract. 2010;89(3):309–319. doi: 10.1016/j.diabres.2010.04.012. [DOI] [PubMed] [Google Scholar]
  • 38.Mendez-Sanchez N, Chavez-Tapia NC, Motola-Kuba D, Sanchez-Lara K, Ponciano-Rodriguez G, Baptista H, Ramos MH, Uribe M. Metabolic syndrome as a risk factor for gallstone disease. World J Gastroenterol. 2005;11(11):1653–1657. doi: 10.3748/wjg.v11.i11.1653. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Mendez-Sanchez N, Bermejo-Martinez LB, Vinals Y, Chavez-Tapia NC, Vander Graff I, Ponciano-Rodriguez G, Ramos MH, Uribe M. Serum leptin levels and insulin resistance are associated with gallstone disease in overweight subjects. World J Gastroenterol. 2005;11(39):6182–6187. doi: 10.3748/wjg.v11.i39.6182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Phillips LS, Harp JB, Goldstein S, Klein J, Pao CI. Regulation and action of insulin-like growth factors at the cellular level. Proc Nutr Soc. 1990;49(3):451–458. doi: 10.1079/pns19900053. [DOI] [PubMed] [Google Scholar]
  • 41.Cai HH, Sun YM, Bai JF, Shi Y, Zhao HL, Miao Y. Relationship between the GH-IGFs axis and the proliferation of bile duct cancer cell line QBC939 in vitro. Hepatobiliary Pancreat Dis Int. 2008;7(1):76–81. [PubMed] [Google Scholar]
  • 42.Alvaro D, Barbaro B, Franchitto A, Onori P, Glaser SS, Alpini G, Francis H, Marucci L, Sterpetti P, Ginanni-Corradini S, et al. Estrogens and insulin-like growth factor 1 modulate neoplastic cell growth in human cholangiocarcinoma. Am J Pathol. 2006;169(3):877–888. doi: 10.2353/ajpath.2006.050464. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.Pazzi P, Scagliarini R, Gamberini S, Pezzoli A. Review article: gall-bladder motor function in diabetes mellitus. Aliment Pharmacol Ther. 2000;14(Suppl 2):62–65. doi: 10.1046/j.1365-2036.2000.014s2062.x. [DOI] [PubMed] [Google Scholar]
  • 44.Hsing AW, Gao YT, Han TQ, Rashid A, Sakoda LC, Wang BS, Shen MC, Zhang BH, Niwa S, Chen J, et al. Gallstones and the risk of biliary tract cancer: a population-based study in China. Br J Cancer. 2007;97(11):1577–1582. doi: 10.1038/sj.bjc.6604047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Aune D, Vatten LJ. Diabetes mellitus and the risk of gallbladder disease: a systematic review and meta-analysis of prospective studies. J Diabetes Complicat. 2016;30(2):368–373. doi: 10.1016/j.jdiacomp.2015.11.012. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

All data generated in this analysis are available from the corresponding author.

Articles from BMC Cancer are provided here courtesy of BMC

RESOURCES